by Isabella Colonna
For December we selected Yau WW, Kirn DR, Rabin JS, Properzi MJ, Schultz AP, Shirzadi Z, Palmgren K, Matos P, Maa C, Pruzin JJ, Schultz SA, Buckley RF, Rentz DM, Johnson KA, Sperling RA, Chhatwal JP. Physical activity as a modifiable risk factor in preclinical Alzheimer’s disease. Nat Med. 2025 Nov 3. doi: 10.1038/s41591-025-03955-6. Epub ahead of print. PMID: 41184638.
In some cases, Alzheimer’s disease (AD) may be potentially preventable or delayed by addressing modifiable risk factors, among which physical inactivity plays a particularly important role.
In this observational study, 296 cognitively unimpaired older adults from the Harvard Aging Brain Study cohort were assessed using pedometer-measured physical activity, longitudinal amyloid-β (Aβ) and tau positron emission tomography (PET) imaging, and annual cognitive evaluations over a follow-up period of up to 14 years.
At baseline, higher physical activity was associated with younger age and male sex but showed no correlation with initial Aβ or tau burden, nor with cognitive performance. Longitudinal analyses revealed no significant relationship between baseline physical activity and subsequent Aβ accumulation. In contrast, greater physical activity was linked to slower cognitive decline, as measured by the Preclinical Alzheimer’s Cognitive Composite-5 (PACC-5), and to slower tau accumulation, whether dependent on Aβ or not. Furthermore, higher physical activity was associated with slower Aβ–related functional decline, assessed using the Clinical Dementia Rating–Sum of Boxes (CDR-SOB).
Moderated mediation analyses indicated that, among individuals with elevated baseline Aβ, slower tau accumulation in the inferior temporal lobe largely accounted for the association between higher physical activity and slower cognitive decline, while only partially mediating the relationship between physical activity and functional decline.
Dose–response analyses revealed a curvilinear relationship between physical activity and both tau accumulation and cognitive decline, with benefits increasing up to a moderate activity level (5,001–7,500 steps per day), beyond which the effects plateaued.
Overall, these findings suggest that interventions targeting physical inactivity could represent a promising strategy in future randomised clinical trials aimed at slowing tau progression and cognitive decline in preclinical AD. They also provide an achievable physical activity target for sedentary older adults at high risk of cognitive decline.
